As a young child, she lived in an Italianate/Mansard-style home in the Ashmont Hill section of Dorchester, Massachusetts and attended the local Girl's Latin School. The home later burned down, but a plaque at Welles Avenue and Harley Street proclaims "Rose Fitzgerald Kennedy Square". The plaque was dedicated by her son, Senator Ted Kennedy, on Kennedy's 102nd birthday in 1992.

Joseph provided well for their family, but was unfaithful. His affairs included one with Gloria Swanson. While eight months pregnant with the couple's fourth child Kathleen, Rose temporarily went back to her parents, but returned to Joseph. In turning a blind eye to her husband's affairs, Rose depended heavily on medication. Ronald Kessler found records for prescription tranquilizers Seconal, Placidyl, Librium, and Dalmane to relieve Rose's nervousness and stress, and Lomotil, Bentyl, Librax, and Tagamet for her stomach.[4]

Rose Kennedy was a strict Catholic throughout her life. Even after her 100th birthday, she rarely missed Sunday Mass and maintained an "extremely prudish" exterior. Her strict beliefs often placed her at odds with her children.[5]Jacqueline Kennedy described her mother-in-law in her correspondence to Father Joseph Leonard, an Irish priest: "I don't think Jack's mother is too bright – and she would rather say a rosary than read a book."[6]

Rose Kennedy stated that she felt completely fulfilled as a full-time homemaker. In her 1974 autobiography, Times to Remember, she wrote, "I looked on child rearing not only as a work of love and a duty, but as a profession that was fully as interesting and challenging as any honorable profession in the world and one that demanded the best I could bring to it..... What greater aspiration and challenge are there for a mother than the hope of raising a great son or daughter?"[5]

After her son John became President in 1961, Rose "became a sort of quiet celebrity," appearing on the International Best Dressed List.[5] Most of her social activities consisted of involvement in charities and women’s groups. Rose also took brisk ocean swims outside her Cape Cod house in fifty-degree weather.

On January 22, 1995, Kennedy died from complications from pneumonia at the age of 104, having outlived her husband by a quarter of a century. She was survived by five children, 26 grandchildren, and 42 great-grandchildren. Rose Kennedy was interred with her husband at Holyhood Cemetery in Brookline, Massachusetts.